Dietary ginsenoside compound K alleviates renal inflammation and metabolic dysfunction induced by gut microbiota-derived imidazole propionate in diabetic mice

Abstract

Ginsenoside compound K (CK), a gut microbiota-transformed bioactive metabolite from ginseng saponins, exhibits dual roles as a food-derived bioactive and therapeutic agent. This study investigated CK's capacity to counteract imidazole propionate (IMP)—a microbial histidine metabolite linked to diabetic kidney disease (DKD). Diabetic male db/db mice received daily intraperitoneal IMP injections (16 mg/kg) to exacerbate DKD, alongside CK oral administration (20 mg/kg) for 17 weeks. IMP aggravated renal dysfunction (serum creatinine: +33 %; urinary albumin: +41 %; vs. db/db controls, p < 0.001), while CK significantly reversed these effects (−49 % and −53 %, p < 0.001 respectively). Mechanistically, IMP activated the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in renal tissues, elevating pro-inflammatory cytokines (interleukin-1β (IL-1β): +57 %; tumor necrosis factor-α (TNF-α): +45 %; p < 0.01), whereas CK suppressed TLR4 signaling (−50 % phosphorylation of inhibitor of NF-κB α (IκB-α), p < 0.05) and shifted macrophage M2 polarization (cluster of differentiation 163+ cells: +3.3-fold, p < 0.001). Critically, CK's prebiotic-like effects were evidenced by its interaction with gut microbiota-derived IMP, disrupting the “dysbiosis-metabolite-inflammation” axis characteristic of metabolic syndrome. In vitro, CK blocked IMP-induced NF-κB activation in macrophages and renal mesangial cells, confirming direct anti-inflammatory targeting. These findings position CK as a novel dietary bioactive that concurrently addresses gut microbiota imbalance and metabolic organ inflammation. By elucidating the CK-IMP-TLR4 interplay, this work advances the application of food-origin ginsenosides in preventing microbiota-related metabolic disorders, offering dual utility in functional foods and DKD therapeutics.